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The agents work for Katherine Marlowe and are fiercely loyal adherents of the clandestine organisation she heads, employing special forces and covert ops training to confound their opponents. All of them are usually dressed in designer suits and are the most well equipped opponents Drake has faced so far. They are also shown to be capable of the acrobatics Drake displays when trying to murder him in Colombia. Although the skins for the agents don't vary considerably, their AI is determined by their weapons. For example, shotgunners will rush the player etc...

There are three variations of Agents. The first and most common type are standard and elite Agents, who use a variety of weapons and use cover intelligently. They will also throw grenades if Drake stays behind cover for extended periods. The second type are armored soldiers carrying shotguns or M9s - these types of enemies will slowly walk towards Nate whilst shooting at him. The third and rarest Agent is the Brute. In the Co-op Adventure there is also a fourth type of agents, who are dressed in white suits and wear gas masks, they carry a pistol but will more often than not just try to strangle the player, requiring the co-op partner to shoot them.